Vacuum freeze-drying, also known as freeze-drying, is a drying method, by which materials are frozen to below the eutectic point temperature and moisture in the materials is removed by sublimation in a low pressure state; it is especially suitable for extending the shelf life of biological preparations such as protein, vaccines and microbes, and improving the quality thereof. The general drying method is to change the moisture in a material from the liquid to the gaseous, while the freeze-drying method is to convert the moisture in the material from the liquid to the solid and then from the solid to the gaseous. Water freezing is an exothermic process, while ice sublimation is an endothermic process, so a freeze-drying system is mainly composed of three operations of refrigerating, heating and vacuuming.
Freezing is the shortest stage in the freeze-drying process, but it affects effects of several key steps such as sublimation, desorption and the freeze-drying throughout the process, such as shape and porosity of a cake, protein polymerization, and the like. Drying, as a long stage in the freeze-drying process, is divided into two small stages, a first drying stage (sublimation) and a second drying stage (desorption).
The size of the ice crystals in the freezing process determines the size of voids in the drying matrix, i.e., it determines the sublimation rate; however, the desorption rate is mainly determined by the specific surface area of the ice crystals. The bigger the ice crystals, the faster the heat transfer, and so the shorter the sublimation time; the larger the specific surface area, the easier the evaporation of the unfrozen water, i.e., the shorter the desorption stage. In general, a large degree of supercooling, i.e., there is a large gap between the equilibrium freezing point temperature and the nucleation temperature, will result in a lot of small ice crystals having a large specific surface area, that is, the first drying stage is slow, while the second drying stage is fast. However, a small degree of supercooling, i.e., the nucleation temperature is controlled to be close to the equilibrium freezing point temperature, will result in a lot of big ice crystals having a small specific surface area, that is, the sublimation is rapid and the desorption is slow. Controlling the nucleation step and removing different sublimation and desorption dynamic performances caused by the random nucleation temperature not only ensure the controllability of the drying process, but also further ensure the quality of the freeze-dried products. In short, the freezing stage affects the efficiency of the entire freeze-drying process and the quality of the products, such as protein stability.
Drying is the most energy-consuming stage in the freeze-drying process; since there is no convection in the vacuum environment, heat transfer and mass transfer are slow, and a common heating plate has a long heating cycle and large energy consumption. Semiconductor, which is a special material, can be used to increase and decrease temperature of 12 V direct current output fixed at heating and refrigerating commons and a commutation circuit composed of a relay, in a fast, timesaving and energy-saving way.
The biological preparations that are efficient but difficult to dissolve often use liposomes as a carrier to increase their clinical effects, and for such medicines a freeze-drying method is often used to obtain a freeze-dried powder, a freeze-dried needle and so on that have storage stability, high activity, and easy transport. At present, the commonly used auxiliary freeze-drying methods include the addition of a nucleation reagent in the freezing stage, and the novel ultrasonic treatment to control the nucleation temperature and the degree of supercooling. For the high activity of the biological medicines, the shorter the freeze-drying time, the better; the lower the water content of the finished products, the better; and the finer and more uniform the formed ice crystals, the better. Therefore, the prior art freeze-dried liposome medicines have the following drawbacks:
(1) An ordinary freeze-drying method cannot control the ice crystal growth in the freezing stage, that is, nucleation randomness, shape difference, and the like occur; besides, the size of ice crystals further affects the drying time, and the larger ice crystals may pierce cells in the freezing process to result in loss of drug efficacy. Inconsistent size of the ice crystals leads to unguaranteed uniformity of quality.
(2) For the freeze-drying method with an additional nucleation reagent, the addition of the nucleation reagent has complex parameters, difficult operation and high cost.
(3) The emerging ultrasound-assisted freeze-drying technology is prone to weakening the drug efficacy due to a lot of instantaneous latent heat caused by ultrasound; and the ultrasound function can be exhibited only in the presence of ultrasound media, which will greatly affect the design of an ultrasonic-freeze-drying integrative machine and bring great inconvenience; in addition, the noise caused by ultrasound is also very harsh.
(4) The conventional condensation-refrigeration system of a water sink is slow in heat transfer and needs long freezing time; the conventional heating system composed of a common heating plate needs long drying time, is energy consuming, and has a certain impact on the quality of the finished products.
(5) Neither a common nor a novel freeze-drying method can change the water content within a sample in the freeze-drying system, thereby reduce the freezing and drying time, and further control the nucleation and the quality of the finished products.